Parkinson's disease (PD) is marked clinically by asymmetrical presentation of motor dysfunction, pathologically by the nigrostriatal dopamine (DA) neuronal loss in the basal ganglia (BG), and often is accompanied by extranigral, non-dopaminergic, non-motor symptoms. The pathogenesis of most PD is unproven, and there are no therapies proven to slow, arrest, or reverse cell death and disease progression. Moreover, both the understanding of PD-associated cell loss and evaluation of potential neuroprotective therapies have been hindered by the lack of a reliable, objective, in vivo marker for cell loss associated with PD progression. The best available in vivo techniques are functional radioimaging (PET & SPECT), assessing either DA transporter density or neuronal activity. While valuable, these endpoints reflect DA cell loss indirectly, are modulated by the symptomatic treatments in PD, are not able to assess non-dopaminergic systems, and are not widely available. Alternatively, structural volumetric imaging can reflect in vivo macroscopic atrophy (caused by cell loss), is less likely to be influenced by purely symptomatic treatments, can assess extranigral/nondopaminergic systems, and is widely available. Yet this approach has not been as exhaustively explored because of the difficulty in relating atrophic changes to a specific mechanism or function; and because of inconsistent findings in prior structural imaging studies in PD. The latter may be a result of cross-sectional designs, small sample sizes, and/or imaging analysis methods with low reliability. Our goal is to pursue structural imaging studies in PD, thus providing a more sophisticated understanding of PD-related cell loss, and a determination of whether MRI can be a useful and non-invasive marker of disease progression. Supported by strong preliminary data, our central hypothesis is that PD patients undergo significant brain atrophic changes focally (e.g., in BG structures) and globally relative to a normative age-matched sample. Not only can these changes be quantified reliably using high resolution MRI coupled with sophisticated analysis techniques, but they may have functional implications that are relevant to PD at both the clinical and heuristic levels. We propose to do longitudinal studies of a cohort of 80 PD subjects within 10 years of clinical diagnosis, and 54 Controls (matched 3:2 in age, gender, handedness, & education). Our aims are to: 1) Establish the age trend of lateral ventricle enlargement and select BG regional atrophy in PD patients compared to Controls; 2) Characterize the lateralization and time-course of longitudinal volumetric changes of lateral ventricles and select BG regions during the course of PD progression in relation to PD motor asymmetry and duration; 3) Explore the potential of the volumetric measures of different structures of interest as a marker(s) of individual aspects of PD motor and non-motor dysfunction during the disease progression; and 4) Explore the interrelationships of changes among different brain regions and PD-related functional changes. PUBLIC HEALTH RELEVANCE: Parkinson's disease (PD) is an age-related neurological disorder that affects about one million Americans' quality of life by causing motor and other dysfunctions, despite patients being on the best treatments available. Understanding the exact cause, and assessing a treatment to slow, or stop, the progression of the disease are hindered by the lack of a widely available, yet reliable, marker for its progression as it unfolds in PD patients. The goal of this grant is to establish MRI measurements as such a marker, thereby leading to a better understanding of the cause of PD and improved assessment of potential neuroprotective agents in PD.